PROJECT SUMMARY/ABSTRACT Problematic alcohol use (ALC) has devastating consequences for individuals, families and society. It is imperative to illuminate the poorly understood genetic basis of ALC to improve the precision of prevention and treatment. Research shows that heritable adolescent precursors to ALC are conduct problems (CP), depression (DEP), and particularly their co-occurrence. Moreover, temperament provides important clues to the diverse genetic origins of CP and DEP. This suggests that combinations of CP and DEP symptoms and temperament characteristics may yield novel, genetically-distinct traits that could become new, more precise targets of ALC prevention. The research targets analysis of four prospective cohorts that will be integrated using advanced data harmonization: Adult and Family Development Project (PI: Chassin), Michigan Longitudinal Study (PI: Zucker), Tracking Adolescents? Individual Lives Survey (PI: Oldehinkel), and Avon Longitudinal Study of Parents and Children (PI: Timpson). Collectively, these datasets provide multigenerational extended pedigrees densely affected with ALC, genomic data, longitudinal data spanning 10+ years, and rich phenotyping of key measures that are similar or identical across cohorts. Aim 1 will examine patterns by which symptoms of CP and DEP and temperament characteristics are inherited, thus identifying highly heritable traits underlying ALC. Aim 2 will employ group-based multi-trajectory modeling of these heritable traits across adolescence (ages 11-18) and relate them to ALC outcomes into adulthood. In Aim 3, sex differences in the multi-trajectory groups and in their associations with ALC will be examined. The complementary research and training aims will be instrumental in launching the candidate?s independent research program on the genetics and development of alcohol use disorder (AUD). The proposed award will provide training in an optimal scientific environment, the University of Pittsburgh, across several key areas: (1) quantitative genetics, large-scale genotypic analysis, genetics of AUD, and other advanced methods with Dr. Bernie Devlin, primary mentor and expert in statistical genetics, and Dr. Arpana Agrawal, consultant and expert in the genetics of AUD; (2) development of AUD and comorbid psychopathology into adulthood with Dr. Brooke Molina, co-mentor and expert in AUD and comorbidity; and (3) data harmonization through consultation with Dr. Patrick Curran, an expert in longitudinal data harmonization. This training will equip the candidate to conduct powerful genetic studies, to take advantage of ever-increasing open data, and to contextualize genetic influences on AUD. With the support of this award, the candidate will gain skills to conduct genetically-informative research that will improve the precision of identification for adolescents at-risk for AUD. This program of research has the potential to advance the field by producing insights into AUD etiology that could eventually inform precision-medicine based prevention.